Project Summary The incidence of renal cell cancer has been rising steadily and for those that have tumor recurrence after surgery, the prognosis is generally poor. In 2013 an estimated 65,150 new cases and 13,680 deaths will be attributed to renal cancer in the United States. Renal cancer is the most common malignancy of the adult kidney and accounts for 2-3% of all adult malignancies. Of these, 33% of patients have metastatic disease at presentation, and 40% of the individuals undergoing a surgical resection eventually develop metastases. Of those who develop metastatic renal cancer, treatment options are limited, with typical median-survival rates between 7-9 months. In recent years, significant improvements in metastatic renal cancer treatment have been reported with the use of immunotherapy and targeted therapies; however, for those who do not respond to these treatments or are not eligible for them, the prognosis is dismal. Recent alternatives in cancer treatment include antibody-drug conjugates (ADC's), where an antibody of an over-expressed cancer antigen is attached through a degradable linker to a cytotoxic drug. To date, all ADCs use a single mechanism of action (MOA) by which the drug is directed to the cancer cell via an antibody. The ADC is then internalized into a lysosome and degraded enzymatically to release the drug, which kills the cancer cell by attacking microtubule formation. While of great interest, instability of linkers that result in off- target drug toxicities, have resulted in FDA approval of only three ADC's; MyloTarg(R) (acute myeloid leukemia), ADCETRIS(R) (Hodgkin lymphoma), and Kadcyla(Breast Cancer) of which, MyloTarg(R) was removed from market due to off-target toxicities associated with linker instability. The novel technology outlined in this proposal was inspired by the emerging ADC field and the naturally occurring cardiac glycosides. This project details the use of a unique and powerful Extracellular Drug Conjugate or EDC. EDC's differ from conventional ADC's in that 1) both the antibody and drug have extracellular site specificity for cancer cells, 2) its activity is based entirely on extracellular binding, eliminating the need for internalization and 3) the linker is non-degradable and serum stable, reducing the potential for off- target toxicities. This Phase I proposal will focus on the use of this novel class of ADC's in treating renal cancer. The end goal of this project will be to develop an EDC for the treatment of metastatic renal cancer which shows an increase in performance, efficacy and safety when compared to current chemotherapeutic treatments, with the intent of improving patient survival outcomes.